Process for making chiral 1,4-disubstituted piperazines

ABSTRACT

A process for a stereoselective preparation of novel chiral nitrogen mustard derivatives useful in synthesizing optically active 1,4-disubstituted piperazines of formula:  
                 
wherein R, Ar, and Q are defined as set forth herein, and intermediate compounds therefor. The 1,4-disubstituted piperazines act as 5HT1A receptor binding agents useful in the treatment of Central Nervous System (CNS) disorders.

This application is a divisional of co-pending application Ser. No.11/147,055, filed on Jun. 7, 2005, which is a divisional of applicationSer. No. 10/384,837, filed on Mar. 10, 2003, which claims priority fromco-pending provisional application Ser. No. 60/363,458, filed on Mar.12, 2002, the entire disclosure of which is hereby incorporated byreference.

BACKGROUND OF THE INVENTION

Piperazines of formula A

wherein R is a lower alkyl, Ar is an unsubstituted or substituted arylor heteroaryl, and Q is a hydrogen, CO-(lower) alkyl, CO-cycloalkyl, orCO-aryl, are potent 5HT1A receptor binding agents. U.S. Pat. No.6,127,357 teaches such piperazine derivatives that are useful in thetreatment of Central Nervous System (CNS) disorders. Piperazinederivatives of formula A contain an asymmetric carbon so they may existin two optically active forms. It is now well understood thatenantiomers bind to receptors with different potency and selectivity,they may have different metabolic fate and produce different sideeffects. WO 9703982 teaches that preferred enantiomers of piperazines offormula A display improved 5HT1A binding affinity and bioavalability.Therefore, an efficient, operationally facile, inexpensive and safealternative process for making these homochiral piperazines isdesirable.

WO 9533725 teaches a method for synthesizing some chiral piperazines offormula A by alkylation of the corresponding 1-aryl-piperazine withenantiomerically pure2-(5-methyl-2,2-dioxido-1,2,3-oxathiazolidin-3-yl)pyridine.

One conventional approach to creating 1,4-disubstituted piperazines isvia bis-alkylation of primary amines with bis(2-chloroethyl) amines, theso-called nitrogen mustard gases. A few optically active piperazines,structurally unrelated to formula A, have been prepared by condensationof an N-substituted bis(2-chloro-ethyl)amine with a selected chiralamine according to Natsuka et al. in J. Med. Chem. 1987,1779 and WO9424115, and with a natural amino acid according to Acta Pol.Pharm.1999, 56, p.41; CA 131: 157745. However, there is a need for aprocess to make synthetically useful, chiral nitrogen mustard molecules.Chem. & Pharm. Bulletin Japan 1954, 275 describes a conversion ofbis(2-chloroethyl)amine into N-bis(2-chloroethyl) aminoacetonitrile, anda related paper in Chem. & Pharm. Bulletin Japan 1957, 487 reports anunsuccessful attempt to resolve the corresponding racemicN-bis(2-chloroethyl)alanine, and tedious resolution of2-[N-bis(2-chloro-ethyl)amino]propanamide.

Polyfunctional chiral amines are accessible by several multi-stepprocedures, but a direct displacement of a reactive functional grouptypically results in racemic amines.

Effenberger et al. (Angew. Chem. 1983, 95[1], 50) reported thattriflates react with simple secondary amines under Walden inversion.This process was applied to the syntheses of both (R)— and (S)-α-aminoacid esters. The method allows asymmetric formation of C(α),N-bond in asingle reaction with a high degree of stereoselectivity, and has beenoccasionally used with minor modifications (Quadri et al., Biorg. & Med.Chem. Letters 2, 1661, 1992; Taylor et al., Tetrahedron Letters 37,1297, 1996). Hoffman and Hwa-Ok Kim, Tetrahedron Letters 31, 2953, 1990replaced triflates with (4-nitrobenzene)sulfonyloxy esters in a reactionwith hydrazines.

SUMMARY OF THE INVENTION

The present invention comprises a process for the preparation of acompound of formula III

wherein R and R′ each independently represents a C₁-C₃ alkyl group; Arrepresents a dihydrobenzodioxinyl or benzodioxinyl, or phenyl optionallysubstituted with up to three substituents independently selected fromhalogen, methoxy, halomethyl, dihalomethyl and trihalomethyl;

-   said process comprising reacting a compound of formula Ia and a    compound of formula Ib to form a compound of formula II,    and further reacting the compound of formula II with an aryl amine    compound, Ar—NH₂, in which Ar is defined as stated above, to produce    a compound of formula III. Preferably, these steps are performed in    a concatenated manner to form compound III without isolating    intermediate compound II.

In a preferred embodiment, the compound of formula Ia is a singleenantiomer, (S) or (R), that leads to the formation of a singleenantiomer of a compound of formula II having an inverted configuration,i.e. (R) or (S). Hydride reduction of compound of formula III thenproceeds with retention of configuration to form the intermediatecompound of formula IV.

The invention further comprises the reaction of a compound of formula IVto form the intermediate compounds of formulae V:

where X is a leaving group such as halo (especially chloro and bromo),

-   methansulfonyloxy,-   p-toluenesulfonyloxy, or p-bromophenylsulfonyloxy.

The invention also comprises the novel compounds represented by formulaeII, III, iV and V, and the optical isomers thereof.

The invention also comprises the following process steps, in whichcompound V is used to make compounds VII, VIII and IX:

-   treating the compound of formula V with a compound of formula VI in    an aprotic solvent    wherein M is an alkali metal (e.g., Na, Li, K) and Y represents a    moiety selected from the group consisting of C₁-C₆ alkoxy, C₁-C₆    alkyl, C₃-C₇ cycloalkyl and C₃-C₇ cycloalkoxy;-   treating the compound of formula VII with a protic acid to form a    compound of formula VIII    and, treating the compound of formula VIII with an aroyl compound    selected from aroyl chloride, aroyl bromide and aroyl anhydride, in    the presence of a base, to form a compound of formula IX    wherein Aryl represents a C₆-C₁₂ aromatic group optionally    substituted with up to three substituents independently selected    from the group consisting of halogen atoms, alkyl, alkoxy,    alkoxycarbonyl, nitro, amino, alkylamino, dialkylamino, haloalkyl,    dihaloalkyl, trihaloalkyl, nitrile and amido substituents each    having no more than six carbon atoms.

DETAILED DESCRIPTION

The present invention provides a process for preparing specificenantiomeric compounds as intermediates in the formation of1,4-disubstituted piperazines that are useful as serotonin 1Areceptor-binding agents. Chiral nitrogen mustard derivatives serve asprimary reactants. This process results in a simpler reaction sequencethan was previously known. The novel synthesis of chiral1,4-disubstituted piperazines generates storage stable, syntheticintermediates for compounds of formula IX, shown above.

Various aspects of a preferred embodiment of the present invention areshown in Scheme 1:

Referring to Scheme 1, (S)-2-[(methylsulfonyl)oxy]propionate iscommercially available, or such lactate triflates can be readilyprepared from the corresponding alkyl lactates, for example according tothe procedures of Prasad et al., J. Chem. Soc. Perkin Trans I, 1991,3331, and Wang and Xu, Tetrahedron 54, 12597, 1998.Bis(2-chloroethyl)amine is liberated as a free base from itshydrochloride salt. The reaction of the first step in Scheme 1 isconducted in an inert organic solvent in which the starting materialsare soluble, such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane,diethyl ether, tert-butyl methyl ether, methylene chloride,chlorobenzene, trifluoromethylbenzene, or toluene. The temperature isnot critical, and suitably may be from 0° C. to about 50° C., preferablybetween ice-bath and room temperature. Higher temperatures promote anundesirable elimination process. The reaction is generally run for 4-6hours, although prolonged stirring times of up to 18-24 hours are notdetrimental. Yields of the corresponding compound of formula II may beas high as 83%, but more typically, yields are in the range of 50-65%.Tetrahydrofuran is an optimum solvent, however, it is very sensitive tothe presence of traces of triflic acid or triflic anhydride that mayinitiate partial tetrahydrofuran polymerization, and the resultinggelatinous material complicates isolation of the product.

A preferred embodiment of this invention comprises a one-step processwherein compound II is prepared in chlorobenzene as a crystallinetriflic salt and is used to alkylate 2,3-dihydro-1,4-benzodioxin-5-aminein chlorobenzene to form compound III. The compound of formula II may bereacted with 2,3-dihydro-1,4-benzodioxin-5-amine in refluxingchlorobenzene for a period about 8 to about 18 hours. The formation ofthe compound of formula III thus may be effected in a concatenatedmanner by using a chlorobenzene solvent and continuing without anecessity for interim isolation of the compound of formula II.

An aminoester of the compound of formula III can be isolated as a freebase or converted to a stable hydrochloride salt. Alternatively, thecompound of formula III is obtained by condensation of2,3-dihydro-1,4-benzodioxin-5-amine with a free base of compound offormula II under similar conditions, and both intermediates II and IIIare used in a crude state in the subsequent steps.

A preferred embodiment for formation of the compound of formula III fromthe compound of formula II comprises the reaction withamino-benzodioxine as illustrated in Scheme I. In another embodiment ofthis invention, an amino-phenyl is used instead of theamino-benzodioxane, wherein the phenyl may be substituted with up tothree substituents independently selected from halogen, methoxy,halomethyl, dihalomethyl and trihalomethyl.

Intermediates of the compound of formula III can be reduced to thealcohol of formula IV by the use of reducing agents. The reaction isperformed by conventional methods well known to those skilled in art,for example by using a complex metal hydride or a boron reducing agentunder non-epimerizing conditions.

In a preferred embodiment of the process of this invention, thereduction is carried out under reflux in ether or in tetrahydrofuran at20-40° C., using lithium aluminum hydride. The enantiomeric purity ofthe isolated alcohol IV is 98% or greater, as determined on a chiralcolumn using a sample of racemic IV as reference.

In a further aspect of this invention, the alcohol of the compound offormula IV may be treated with methanesulfonyl chloride in the presenceof an organic base in methylene chloride to produce the intermediatecompound of formula V. In an alternative embodiment, the alcohol offormula V or its hydrochloride salt is heated with thionyl chloride inrefluxing chloroform to obtain a hydrochloride salt of the compound offormula V.

Depending on the nature of the leaving group X, acidity of the medium,concentration, or solvent polarity, these piperazines may exist in anequilibrium with 6-aza-3-azoniaspiro[2,5]octane species.

The present invention further comprises the novel compounds of formulaII, III, and IV. Preferred embodiments thereof include:

-   N,N-bis(2-chloroethyl)-(R)-alanine methyl ester,    trifluoromethanesulfonate;-   N,N-bis(2-chloroethyl)-(R)-alanine ethyl ester,    trifluoromethanesulfonate;-   (R)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-α-methyl-1-piperazineacetic    acid ethyl ester;-   (R)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-α-ethyl-1-piperazineacetic    acid ethyl ester;-   (R)4-(2,3-dihydro-1,4-benzodioxin-5-yl)-α-methyl-1-piperazineacetic    acid methyl ester;-   (R)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-α-ethyl-1-piperazineacetic    acid methyl ester;-   (R)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-β-methyl-1-piperazineethanol;    and,-   (R)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-β-ethyl-1-piperazineethanol.

Compound V can be reacted with a compound of formula VI to form acompound of formula VII. Y represents a moiety selected from the groupconsisting of C₁-C₆ alkoxy, C₁-C₆ alkyl, C₃-C₇ cycloalkyl and C₃-C₇cycloalkoxy.

The aminopyridyl functionality is introduced via displacement. It is notapparent from the prior art how seriously the side reactions describedabove can threaten the usefulness of this displacement. Much depends onthe specific alkylating reagent. In WO9703982, an aminopyridine VIa,under unspecified conditions, can be treated with generic compounds Va,where X is a leaving group, to give VIIa. In the course of developingthis invention, we have observed that the anion of N-alkanoyl compounds(i.e., VIb) reacts with V (X═Cl) to give a significant quantity (ca.20%) of undesired alkylation on the pyridyl nitrogen, forming compoundX. In a preferred embodiment of the present invention, Y is an alkoxygroup, more preferably C₁-C₆ alkoxy.

This invention provides a practical synthesis of N-aryl piperazineswhere chirality is introduced at the piperazine ring formation step and2-aminopyridyl substitution is incorporated via displacement.

The use of t-Boc 2-amino pyridine, VI, as described in this inventionsignificantly suppresses the amount (<7%) of analogous by-productformed, increasing the proportion of desired compound VII. As shown inthe preceding section, the t-Boc protecting group is easily removed andthe freed amine can be then acylated.

Throughout this specification and in the appended claims, except whereotherwise indicated, the terms halogen and halo refer to F, Cl and Br,and the terms alkyl, alkane, alkanol and alkoxy include both straightand branched chain alkyl groups.

The following examples are presented to illustrate certain embodimentsof the present invention, but should not be construed as limiting thescope of this invention.

EXAMPLE I N,N-Bis(2-chloroethyl)-(R)-alanine ethyl ester,trifluoromethanesulfonate

A suspension of bis(2-chloroethyl)amine hydrochloride (0.392 g; 2.1mmol) in 5N aqueous sodium hydroxide (3 mL) is extracted with ether(2×10 mL) and the combined extracts are washed with a minimum amount ofwater and saturated brine. The ethereal solution is dried quickly overmagnesium sulfate and filtered. Tetrahydrofuran (2 mL) is added to thefiltrate, and ether is carefully removed under reduced pressure on arotavapor unit without heating. The residue is mixed with a solution ofethyl (S)-2-[(methylsulfonyl)oxy]-propionate (0.5 g; 2 mmol) intetrahydrofuran (1 mL). After stirring the reaction mixture for 24 hrsat room temperature, there is no visible precipitate. The volatiles areremoved under reduced pressure and the remaining viscous oil isdissolved in ether (8 mL), and the slightly turbid solution is filteredafter 60 minutes. The filtrate is treated dropwise with n-heptane toinduce crystallization; the final ratio of n-heptane/ether is 1:3. Thecrystalline salt is collected by filtration and washed quickly with asmall portion of ether. There is obtained 0.653 g (yield 83.3%) ofN,N-bis(2-chloroethyl)-(R)-alanine ethyl ester,trifluoromethanesulfonate; mp 73-74.5° C.; ¹H NMR (300 MHz, CDCl₃) *1.35 (t, J=7.1 Hz, 3H), 1.76 (d, J=7.2 Hz, 3H), 3.87 (m, 2H), 4.00 (m,2H), 4.35 (q, J=7.1 Hz, 2H), 4.57 (q, J=7.2 Hz, 1H), 9.02 (b, 1H).

EXAMPLE II(R)-4(2,3-Dihydro-1,4-benzodioxin-5-yl)-α-methyl-1-piperazineacetic acidethyl ester

A solution of 2,3-dihydro-1,4-benzodioxin-5-amine (0.327 g; 2.16 mmol)in chlorobenzene (2 mL) is added to a solution ofN,N-bis(2-chloroethyl)-(R)-alanine ethyl ester (trifluoromethanesulfonicacid salt; 0.850 g; 2.16 mmol) in the same solvent (2 mL). The stirredreaction mixture is heated at 130° C. for 15 hours, the volatiles areremoved on a rotavap, and the semi-solid residue is partitioned between10% sodium bicarbonate (15 mL) and ether. Organic extracts are washedwith brine, dried over magnesium sulfate, and filtered. TLC (chloroform)shows formation of a new product with R_(F) 0.15,(R)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-α-methyl-1-piperazineaceticacid ethyl ester. Upon addition of 1N ethereal HCl,(R)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-α-methyl-1-piperazineaceticacid ethyl ester is converted into its hydrochloride salt that iscollected by filtration; 0.615 g (80%), mp 168-171° C. The salt can berecrystallized from ethanol-ether, or acetone-ether. ¹H NMR (300 MHz,DMSO-d₆) * 1.25 (t, J=7.1 Hz, 3H), 1.58 (d, J=7.2 Hz, 3H), 3.16 (m, 2H),3.36 (m, 2H), 4.23 (m, 4H), 4.26-4.38 (m, 3H), 4.48 (b, 4H), 6.52 (d,J=7.9 Hz, 1H), 6.57 (d, J=8 Hz, 1 H), 6.76 (t, J=8 Hz, 1H), 11.3 (b,<1H).

EXAMPLE III(R)-4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-β-methyl-1-piperazineethanol

The hydrochloride salt made by Example II (1.07 g; 3 mmol) is suspendedin 5% aqueous sodium bicarbonate (6 mL) and extracted with ether. Theorganic phase is separated, washed with brine, dried quickly overmagnesium sulfate and filtered. The filtrate is added to a stirredsuspension of lithium aluminum hydride (0.34 g; 9 eq) and the mixture isheated to a mild reflux for 3 hours. After cooling, it is decomposedwith water (1 mL) and 0.5N hydrochloric acid (7 mL). The aqueous layeris separated, basified with 10% sodium bicarbonate and re-extracted withether. The combined extracts are washed with small amounts of water andbrine, dried over magnesium sulfate, filtered and evaporated. The oilyproduct (0.69 g; yield 82%) slowly crystallizes upon standing, and canbe recrystallized from n-butanol/n-heptane; mp 92° C.; enantiomericpurity 98%; ¹H NMR (300 MHz, CDCl₃) * 1.03 (d, J=7 Hz, 3H), 2.74 (m,2H),2.97 (m, 3H), 3.14 (m, 4H), 3.42 (t, J=11 Hz,1H), 3.57 (dd, J=11 Hz,J₁=5 Hz, 1H), 4.35 (sym m, 4H), 6.53 (d, J=7.9 Hz, 1H), 6.61 (d, J=7.9Hz, 1H), 6.75 (t, J=7.9 Hz, 1H)

EXAMPLE IV(R)-4(2,3-Dihydro-1,4-benzodioxin-5-yl)-α-methyl-1-piperazineacetic acidethyl ester

A free base of bis(2-chloroethyl)amine is liberated by partitioning itshydrochloride salt between 5N aqueous sodium hydroxide and methylenechloride, in an analogous manner to that used for Example I. Theisolated bis(2-chloroethyl)amine (0.94 g; 6.56 mmol) is then added intwo portions over 1 hour into a stirred solution of(S)-2-[(methylsulfonyl)oxy]propionate (0.82 g; 3.28 mmol) inchlorobenzene (10 mL) at room temperature. The reaction mixture isstirred for additional 2 hours, the solid precipitate is filtered offand washed with a small volume of chlorobenzene. The filtrate is mixedwith a solution of 2,3-dihydro-1,4-benzodioxin-5-amine (0.46 g; 3 mmol)and the reaction mixture is heated to reflux for 18 hours. Aftercooling, the product is rendered basic with 5% aqueous sodiumbicarbonate (20 mL) and extracted twice with ether (50 mL). The combinedextracts are washed with water, brine, dried over magnesium sulfate, andfiltered. The filtrate is concentrated in vacuo to give a crude productthat can be directly reduced, or passed through a plug of silica gel inchloroform to obtain compound III (0.49 g; overall yield 50%). Thematerial is identical to that described in Example II.

EXAMPLE V(R)-4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-β-methyl-1-piperazineethanol

A free base of bis(2-chloroethyl)amine (28.4 g; 0.2 mol) is liberatedfrom its hydrochloride salt as described in Example IV and mixed with asolution of (S)-2-[(methylsulfonyl)oxy]propionate (20 g; 0.08 mol) inchlorobenzene (150 mL). The mixture is stirred for 3 hours at roomtemperature, and the resulting thick slurry is washed with water (100mL) and 10% sodium bicarbonate (100 mL). The organic phase istransferred to a flask containing 2,3-dihydro-1,4-benzodioxin-5-amine(9.6 g; 0.064 mol) and the reaction mixture is allowed to reflux uponstirring for 18 hours. A small amount of yellow precipitate appears. Themixture is cooled to room temperature and agitated with 10% aqueoussodium bicarbonate (55 mL) for 1 hour. The organic layer is separated,dried over sodium sulfate, filtered, and concentra-ted in vacuo. Theresidue is dissolved in tetrahydrofuran (50 mL) and added dropwise to astirred suspension of lithium aluminum hydride (9.1 g; 0.24 mol) intetrahydrofuran (50 mL). The mixture is heated to 40° C. for 90 minutes,cooled, and decomposed by dropwise addition of ethyl acetate (200 mL).The product is then extracted with 2N hydrochloric acid (500 mL), theaqueous portion is washed three times with ethyl acetate (150 mL) andrendered basic with 10N sodium hydroxide to re-extract the product withethyl acetate (2×200 mL). The combined extracts are washed with brine,dried over sodium sulfate, filtered and evaporated in vacuo. Theresidual oil crystallizes upon standing, and in TLC analysis (ethylacetate-hexane 3:2) co-spots with the alcohol of Example III.Spectroscopic data and enantiomeric purity are identical to thosepresented in Example III. Overall yield 9.1 g (51%) based on2,3-dihydro-1,4-benzodioxin-5-amine.

EXAMPLE VI6-(2,3-Dihydro-1,4-benzodioxin-5-yl)-1-methyl-6-aza-3-azoniaspiro[2,5]octanechloride

A solution of the alcohol made according to Example III (0.5 g: 1.8mmol) in methylene chloride (15 mL) is treated with triethylamine (0.2g; 1.98 mmol). The mixture is stirred on a ice bath and a solution ofmethanesulfonyl chloride (0.24 g; 2.1 mmol) in methylene chloride (2 mL)is added dropwise. After 20 minutes, the ice bath is removed, and thereaction mixture is kept at room temperature overnight. The resultingsolution is washed successively with a small amount of water, 5% aqueoussodium bicarbonate, and brine, then dried over magnesium sulfate andfiltred. The volatiles are removed on a rotavap to give an oily product(0.5 g). ¹H NMR (300 MHz, CDCl₃) * 1.55 (d, J=7.2 Hz, 3H), 2.54 (dd,J=15 Hz, J₁=7.5 Hz, 1H), 2.64-2.81 (m, 5H), 3.11 (m, 4H), 4.11 (sym m,1H), 4.27 (m, 4H), 6.52 (d, J=7.8 Hz,1H), 6.57 (d, J=8 Hz,1H), 6.76 (t,J=7.8 Hz,1H)

EXAMPLE VII(R)-4(2,3-Dihydro-1,4-benzodioxin-5-yl)-1-(2-chloro-1-methylethyl)piperazine

A solution of the alcohol made according to Example III (0.3 g: 1.08mmol) in methylene chloride (5 mL) is acidified with ethereal HCl, theresulting solution is evaporated, and the semi-crystalline residuetriturated with ether. After decanting, the material is crystallizedfrom acetonitrile-ether, mp 207-210° C. This salt (0.35 g) is suspendedin chloroform (6 mL), thionyl chloride (0.2 g) is added, and the mixtureis subjected to reflux for 8 hours. The resulting solution is allowed tocool, volatiles are removed in vacuo, and the residue is stripped withtoluene and dried. TLC (ethyl acetate-hexane 3:2) shows no alcoholstarting material present. ¹H NMR (300 MHz, DMSO-d₆) * 1.56 (d, J=7 Hz,3H), 3.45 (m, 6H), 4.64 (m, 2H), 4.75 (m, 1H); the spectrum also showsthe presence of the aziridinium species. The product can be useddirectly for alkylation of 2-(tert-butoxycarbonyl-amino) pyridine.

Many variations of the present invention not illustrated herein willoccur to those skilled in the art. The present invention is not limitedto the embodiments illustrate and described herein, but encompasses allthe subject matter within the scope of the appended claims andequivalents thereof.

1. A compound of formula II

wherein R and R′ each independently represents a lower alkyl of C₁-C₃,and optical isomers and salts thereof.
 2. A compound according to claim1 wherein said salt is:


3. A compound selected from the group consisting ofN,N-bis(2-chloroethyl)-(R)-alanine methyl ester,trifluoromethanesulfonate; and N,N-bis(2-chloroethyl)-(R)-alanine ethylester, trifluoromethanesulfonate; and the optical isomers thereof.